1. Field of the Invention
This invention relates to certain 2,4-diaminoquinazolines. Particularly, the invention relates to certain 7-alkoxy-2,4-diaminoquinazolines which are further substituted by a 6-chloro group and/or an 8-alkoxy group, their use as antihypertensive agents, pharmaceutical compositions thereof and intermediates for their production.
2. Description of the Prior Art
U.S. Pat. Nos. 3,511,836; 3,635,979 and 3,663,706 disclose 6,7-dimethoxy-2,4-diaminoquinazolines of the formula ##STR2## where Z is a nitrogen-containing heterocyclic group. One of these compounds, 2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline, is a clinically useful antihypertensive agent and is marketed under the generic name "prazosin," the pharmacology of which is discussed in Constantine et al., "Hypertension: Mechanisms and Management," edited by Onesti, Kin and Moyer, Grune and Stratton, 1973, pp. 429-444.
U.S. Pat. Nos. 3,669,968 and 3,769,286 disclose 6,7,8-trialkoxy-2,4-diaminoquinazolines in which the 2-amino group is substituted by certain alkyl and hydroxy substituted alkyl groups or is a heterocyclic group such as piperidino or 4-substituted piperazino. One of these compounds is known by the generic name "trimazosin" and has the formula ##STR3## Trimazosin is also an active antihypertensive agent, see e.g., Vlachikis et al., Current Therapeutic Research, 17, 564 (1975). However, it is less potent than prazosin. Althuis et al., J. Med. Chem., 20, 146 (1977) have shown the 6-0-demethyl derivative is a major metabolite of prazosin of considerably lower blood pressure lowering activity. The 7-0-demethyl derivative is a less prevalent metabolite.
U.S. Pat. Nos. 3,920,636 and 4,044,135 disclose homopiperazinoquinazoline compounds as antihypertensive agents.
Several patents have issued which disclose antihypertensive compounds of the general formula ##STR4## U.S. Pat. No. 4,001,237 claims compounds wherein R.sup.a is an oxazole, isoxazole, thiazole or isothiazole radical.
In U.S. Pat. No. 4,001,238, such compounds are disclosed wherein R.sup.a is of the formula ##STR5##
U.S. Pat. No. 3,780,040 discloses 3,4-dihydroquinazoline analogs of the above formula wherein R.sup.a is 2-thienyl.
In U.S. Pat. Nos. 4,026,894 and 4,112,097, R.sup.a is a 2-tetrahydrofuryl or 2-tetrahydropyranyl moiety. U.S. Pat. No. 4,060,615 claims compounds in which R.sup.a is cycloalkyl having 3 to 8 carbon atoms and cycloalkenyl having 4 to 8 carbon atoms. U.S. Pat. No. 4,101,548 is concerned with 1,2,3-thiadiazole amides of the above formula wherein R.sup.a is ##STR6## and R.sup.b is hydrogen, lower alkyl, NH.sub.2 or NHCO.sub.2 R.sup.c in which R.sup.c is lower alkyl.
6,7-Dimethoxy-2-(4-thiomorpholin-1-yl) 4-aminoquinazolines and derivatives in which the 2-substituent is ##STR7## d is 0, 1 or 2 are disclosed as antihypertensive agents in U.S. Pat. No. 4,115,565.
British Pat. No. 1,530,768 discloses prazosin analogs in which the 2-amino group is of the formula ##STR8## where R.sup.e is phenyl, substituted phenyl, furyl, thienyl or 5-alkylthio-1,3,4-oxadiazol-2-yl.
French Pat. No. 2,321,890 discloses analogs of prazosin in which the 2-amino substituent is a piperidino or piperazino group substituted in the 3 or 4 position.
The compounds of the invention are highly potent antihypertensive agents having improved duration of action since they are not susceptible to metabolic demethylation at the 6-position with resultant loss of activity as is the case with prazosin. In addition, the invention compounds have improved water solubility when compared to prazosin. They can therefore be administered intraveneously, particularly for emergency purposes and are uniformly absorbed by all patients.